Despite medical advances, heart failure (HF) remains one of the leading causes of mortality. Patients with HF often end up back in the hospital, suggesting that HF increases the risk of future acute heart problems and contributes to the development of multiple chronic diseases.
A common feature of many chronic diseases is inflammation. Whether heart failure leads to chronic inflammation in various organs and contributes to the development of chronic diseases is not fully understood. However, it is known that innate immune memory can play a role not only in protecting against infections but also in the development of non-infectious diseases.
Macrophages are immune cells that protect against left ventricular overload and maintain normal heart function. Cardiac macrophages are divided into two types: embryonic cells that can self-renew in cardiac tissue and monocytes—cells circulating in the blood. With age and in heart disease, macrophages of embryonic origin are replaced by monocytic macrophages, exacerbating heart failure.
Genetic changes associated with aging also affect macrophages and can contribute to the development of cardiovascular diseases. These changes affect hematopoietic stem cells (HSCs), from which monocytes and macrophages are formed. Thus, changes in the hematopoietic system can substantially impact the heart and other organs.
Scientists from the University of Tokyo (Japan) investigated:
- Whether heart failure causes changes in HSCs and the immune cells derived from them.
- Whether HF contributes to more severe cardiac pathologies and diseases of other organs and tissues, including the kidneys and muscles.
Changes in Stem Cells in Heart Failure Contribute to the Development of Cardiac Pathology, Kidney Disease, and Sarcopenia
Research on mice has shown that heart failure (HF) causes changes in hematopoietic stem cells (HSCs). When HSCs from mice with HF were transplanted into healthy mice, the recipients experienced reduced cardiac function and developed fibrosis.
HSCs from mice with heart failure differed from normal HSCs. These HSCs gave rise to monocytes and neutrophils more frequently and less frequently to macrophages. After bone marrow transplantation from mice with HF, monocytic-origin macrophages often replaced cardiac macrophages in recipient mice. In these macrophages, the activity of genes associated with inflammation was increased.
Thus, heart failure drives HSCs to produce more pro-inflammatory macrophages. Since resident macrophages in cardiac tissue maintain homeostasis and protect the heart from stress, this change in HSCs can disrupt cardiac homeostasis and contribute to pathological structural changes in the heart, exacerbating heart failure.
Changes in HSCs Increase Kidney Vulnerability
There is evidence that heart failure is associated with poor outcomes for the kidneys after acute kidney injury. In the present study, mice receiving bone marrow from HF developed tubular kidney injury and kidney fibrosis. In the kidneys of these mice, pro-inflammatory macrophages of monocytic origin accumulated.
Sarcopenia Is Closely Linked to Heart Failure
Macrophages are essential for muscle regeneration after injury. Four weeks after cardiotoxin injection, the cross-sectional areas of regenerated muscle fibers at the injury site were smaller in mice receiving bone marrow from HF mice than in control mice. The injured muscles ‘ healing and regeneration were impaired, with marked fibrosis observed.
Therefore, changes in HSCs induced by heart failure disrupt tissue homeostasis and stress responses in the heart, kidneys, and skeletal muscles.
Heart Failure Causes Changes in HSCs by Suppressing TGF-β Production
In the bone marrow, HSCs remain quiescent and periodically “wake up” for cell division. The protein TGF-β is essential for maintaining the quiescent state of HSCs. Cardiac pressure overload suppresses TGF-β activation, causing HSCs to divide and alter their function.
Within days after acute myocardial infarction, sympathetic nerves, and hematopoiesis are activated in the bone marrow. This sympathetic hyperactivation is followed by persistent pathology of the sympathetic nervous system in the bone marrow. This sympathetic neuropathy disrupts TGF-β production, leading to HSC division and cardiac dysfunction.
Administering TGF-β suppresses HSC activation caused by heart failure. However, TGF-β promotes fibrosis in many organs, including the heart. Therefore, further studies are needed to assess whether targeting the TGF-β signaling pathway could improve heart failure outcomes.
Conclusion
Changes in hematopoietic stem cells play a vital role in developing heart failure and associated diseases. These changes can exacerbate inflammation and tissue damage, including in the kidneys and muscles, and can persist and be transmitted through bone marrow transplantation. Further research may help develop new treatments for heart failure based on managing hematopoietic stem cell function and their interaction with the immune system.
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Reference
Heart failure promotes multimorbidity through innate immune memory
